Functional Bidirectionality of ERV-Derived Long Non-Coding RNAs in Humans

Human endogenous retroviruses (HERVs) are widely recognized as the result of exogenous retroviruses infecting the ancestral germline, stabilizing integration and vertical transmission during human genetic evolution. To date, endogenous retroviruses (ERVs) appear to have been selected for human physiological functions with the loss of retrotransposable capabilities. ERV elements were previously regarded as junk DNA for a long time. Since then, the aberrant activation and expression of ERVs have been observed in the development of many kinds of human diseases, and their role has been explored in a variety of human disorders such as cancer. The results show that specific ERV elements play respective crucial roles. Among them, long non-coding RNAs (lncRNAs) transcribed from specific long-terminal repeat regions of ERVs are often key factors. lncRNAs are over 200 nucleotides in size and typically bind to DNA, RNA, and proteins to perform biological functions. Dysregulated lncRNAs have been implicated in a variety of diseases. In particular, studies have shown that the aberrant expression of some ERV-derived lncRNAs has a tumor-suppressive or oncogenic effect, displaying significant functional bidirectionality. Therefore, theses lncRNAs have a promising future as novel biomarkers and therapeutic targets to explore the concise relationship between ERVs and cancers. In this review, we first summarize the role of ERV-derived lncRNAs in physiological regulation, mainly including immunomodulation, the maintenance of pluripotency, and erythropoiesis. In addition, pathological regulation examples of their aberrant activation and expression leading to carcinogenesis are highlighted, and specific mechanisms of occurrence are discussed.